Millions of Americans suffer from moderate to severe persistent inflammatory pain, causing physical and emotional suffering. Non-steroidal anti-inflammatory drugs are commonly used for treating inflammatory pain. They are,however, associated with gastrointestinal disturbances and more recently cardiovascular risks. Opioids can be used to manage chronic pain, but their use is limited by adverse effects and the risk of addiction. It has been reported that about 50% of persistent pain sufferers lack effective pain control. Acupuncture, a therapeutic modality of traditional Chinese medicine (TCM), has been used for millenia to treat pain and a variety of other diseases and symptoms. Previous studies have revealed that electroacupuncture (EA)produces prolonged anti-inflammatory and anti-hyperalgesic effects in rats with complete Freund's adjuvant (CFA)-induced inflammatory hyperalgesia, which mimics symptoms seen in patients with chronic inflammatory pain. This project is designed to define the underlying mechanisms of EA- produced anti-inflammation and anti-hyperalgesia. It has been well documented that the Hypothalamus- Pituitary-Adrenal axis (HPA)plays an important role in modulating inflammation and pain. EA'santi- inflammatory effect was attenuated in rats with adrenalectomy. Therefore, we hypothesize that EA activates the HPA axis to release corticosteroid (i.e.corticosterone in rats) that, at least in part, mediates the prolonged anti-inflammatory and anti-hyperalgesic effects. This hypothesis will be tested on the CFA-rat model. The specific aims are: Aim I: Determine ifEA regulates the plasma levels of HPA hormones in the rat model of peripheral inflammation and hyperalgesia. Following EAtreatment, the plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in EA-treated and control rats will be measured and compared at various time points. Aim II: Characterize the role of the adrenal gland in EA-induced anti- inflammation and anti-hyperalgesia. The effects of EA will be evaluated in rats with bilateral adrenalectomy and those given a steroid receptor antagonist, RU486. Aim III:Characterize the role of the pituitary gland in EA-induced anti-inflammation and anti-hyperalgesia. The effects of EA will be evaluated in rats with hypophysectomy and those given an anti-ACTH-peptide, corticostatin-l. Aim IV: Characterize the role of the paraventricular nuclei (PVN) of hypothalamus in EA-induced anti-inflammation and anti-hyperalgesia. The effects of EA will be evaluated in rats with lidocaine-inactivated PVN and those given a corticotropin- releasing factor (CRF) antagonist, astressin. Along with other projects in the Center grant application, the findings will advance our understanding of the mechanisms of acupuncture and TCM and will provide valuable information for designing clinical trials for treating patients with chronic inflammatory pain.